Sodium hydride → (4-[(R)-2-(1-ethoxy-ethoxymethyl)-6-oxo-piperidin-1-yl]-but-2-ynyloxy}-acetic acid methyl ester

HRID 2052957Notes

Reaction equation

HRID 2052957 reaction equation
[H-].[Na+].[CH2:3]([O:5][CH:6]([O:8][CH2:9][C@@H:10]1[NH:15][C:14](=[O:16])[CH2:13][CH2:12][CH2:11]1)[CH3:7])[CH3:4].[CH3:17][O:18][C:19](=[O:27])[CH2:20][O:21][CH2:22][C:23]#[C:24][CH2:25]I.C([O-])(O)=O.[Na+]>CN(C=O)C>[CH3:17][O:18][C:19](=[O:27])[CH2:20][O:21][CH2:22][C:23]#[C:24][CH2:25][N:15]1[C:14](=[O:16])[CH2:13][CH2:12][CH2:11][C@@H:10]1[CH2:9][O:8][CH:6]([O:5][CH2:3][CH3:4])[CH3:7]

Participants

6

Reactant 4

HCID 24758Sodium hydrideHCID 516892Sodium BicarbonateHCID 58961293(R)-6-(1-ethoxyethoxymethyl)-piperidin-2-oneHCID 86012514(4-Iodo-but-2-ynyloxy)-acetic acid methyl ester

Product 1

HCID 69021961(4-[(R)-2-(1-ethoxy-ethoxymethyl)-6-oxo-piperidin-1-yl]-but-2-ynyloxy}-acetic acid methyl esterYield 21%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent3×

Procedure

Sodium hydride (60% dispersion in oil, 278 mg, 6.95 mmol) was added to a solution of (R)-6-(1-ethoxyethoxymethyl)-piperidin-2-one (from example 50, step 1, 1.40 g, 6.96 mmol) in DMF (10 mL) at 0° C. After 1 h at 0° C., (4-iodo-but-2-ynyloxy)-acetic acid methyl ester (2.05 g, 7.65 mmol) in DMF (10 mL) was added via cannula and the reaction was allowed to warm to rt. After 15 min at rt, the reaction mixture solidified, so more DMF (3 mL) was added. After 18 h at rt, the reaction was treated with saturated aqueous NaHCO3 (50 mL) and extracted with EtOAc (3×70 mL). The combined extracts were washed with water (2×50 mL) and brine (2×50 mL) then dried (MgSO4), filtered and concentrated in vacuo. Purification of the residue by flash column chromatography on silica gel (20%→50% EtOAc/CH2Cl2, gradient) afforded 500 mg (21%) of {4-[(R)-2-(1-ethoxy-ethoxymethyl)-6-oxo-piperidin-1-yl]-but-2-ynyloxy}-acetic acid methyl ester.

Workup

  1. waitAfter 15 min at rt
  2. waitAfter 18 h at rt
  3. extractionextracted with EtOAc (3×70 mL)
  4. washThe combined extracts were washed with water (2×50 mL) and brine (2×50 mL)
  5. dry with materialthen dried (MgSO4)
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customPurification of the residue by flash column chromatography on silica gel (20%→50% EtOAc/CH2Cl2, gradient)

Sources & evidence

ORD record
ord-bef233f548f34bf98347796435d5213e
Source dataset
uspto-grants-2008_02
Patent number
US07326716B2

Reaction notes

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